This project employs a new strategy, suggested by basic research in the science of aging, to find small molecules (precursors of drugs) that extend healthy, youthful lifespan and combat age-related diseases such as cancer. In animals, mutations in many nutrient, energy and stress-sensing genes extend youthfulness and lifespan and prevent age-related disease. A shared dream of aging researchers is that these remarkable findings will lead to new ways to keep us more youthful and disease-free as we age. My lab has carried out a small-molecule screen in hopes of bringing this dream closer to reality. Instead of targeting a single aging regulator, we cast a wide net by screening first for a cellular phenotype that is shared by cells from many long-lived animal mutants, as well as cells from long-lived species: increased resistance to multiple forms of environmental stress. When similar screens have been done in animals, a fraction of the hits have proven to extend lifespan. From a screen of 104,000 compounds, we found ~ 50 that make human primary cells in culture resistant to oxidative stress. Some confer resistance to other stressors as well. We are now asking which of these compounds might activate human longevity pathways. So far, at least some small molecules activate pathways that extend lifespan in animals, and at least some appear to increase C. elegans stress resistance and lifespan. A hallmark of many long-lived mutants is cancer resistance, and several of our top hits are predicted to have anticancer activity. Thus this screening strategy may lead to new ways to treat or prevent cancer. We will explore this hypothesis by testing our small molecules for anticancer activity. Relevance: Cancer is an age-related disease, and many gene perturbations that extend lifespan in animals also delay cancer. In this study, we use our knowledge of the basic biology of aging to develop new ways to find drugs against cancer. These drugs should also increase youthfulness and general health.